Combination Therapies May Spur Evolution of the Myelofibrosis Treatment Paradigm

Prithviraj Bose, MD

JAK inhibitor combination therapies may bolster the efficacy of ruxolitinib (Jakafi) monotherapy in patients with myelofibrosis, although further phase 3 research is necessary to define the roles of these combinations and determine how certain patient subsets may benefit from these and other treatment approaches, according to Prithviraj Bose, MD.

The ongoing phase 3 MANIFEST-2 trial (NCT04603495) is exploring pelabresib (CPI-0610) plus ruxolitinib vs ruxolitinib alone in patients with JAK inhibitor–naïve myelofibrosis, with splenic response at week 24 as the primary end point.¹ Additionally, the ongoing phase 3 TRANSFORM-1 trial (NCT04472598) is evaluating spleen volume reduction in patients with JAK-2 inhibitor–naïve disease who receive ruxolitinib with or without navitoclax (ABT-263).²

“Things that previously were felt to be not addressable now at least have the promise of certain novel agents being able to tackle those issues,” Bose said of the myelofibrosis treatment landscape in an interview with OncLive®.

In the interview, Bose discussed the development of non-myelosuppressive JAK inhibitors for patients with myelofibrosis, where the future of combination therapy is headed in this population, and the importance of enrolling patients in clinical trials that are tailored to their disease subset and treatment needs.

Bose is an associate professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What developments have defined shifts in the myelofibrosis treatment landscape?

Bose: The advances have primarily been therapeutic. [We have not had much] change in the diagnostic process or prognostication for patients with myelofibrosis over the past couple of years. There are many prognostic models, but the latest ones were published [around] 2018.

However, suddenly, the landscape is significantly shifting. We’ve had the advent of non-myelosuppressive JAK inhibitors. For example, pacritinib [Vonjo] was approved in February 2022, and momelotinib is expected to be approved in [September] 2023. These JAK inhibitors are not myelosuppressive, allowing for their use in patients with low blood counts.

Furthermore, they have the potential to improve anemia. This has been better appreciated with momelotinib but in late 2022, we learned that pacritinib also inhibits ACVR1/ALK2, [thereby] suppressing the liver’s hepcidin production. That leads to iron being more available for erythropoiesis, which improves anemia. This story of ACVR1 inhibition as a therapeutic approach is gaining ground with pacritinib, an approved drug, and momelotinib, a drug that may be approved with this attribute. [This] is certainly important for patients because we struggle with [managing] anemia; it’s a major unmet need. This has spurred other companies, such as Incyte, to develop their own ACVR1/ALK2 inhibitors. This arena will continue to evolve and is one I’m excited about.

What does the future look like for combination therapies in myelofibrosis?

This is an area of tremendous interest. Many agents are being explored in combinations. Two that come to mind are pelabresib and navitoclax. These are the most advanced in clinical development, both being in phase 3 trials. We are awaiting the readouts in the frontline setting with ruxolitinib, [including] ruxolitinib plus pelabresib vs ruxolitinib and placebo in the MANIFEST-2 trial, and ruxolitinib and navitoclax vs ruxolitinib and placebo in the TRANSFORM-1 trial. Both trials are fully accrued, and we are awaiting these results.

The idea here is that ruxolitinib alone provides patients much benefit regarding spleen symptoms, etc. but [induces] problems with cytopenias. [Ruxolitinib does not] majorly affect bone marrow fibrosis or the driver mutation allele burden. There’s been much interest in finding lab-based synergistic combinations, and these 2 are at the top of the list. Pelabresib is a BET inhibitor. Navitoclax is a BH3-mimetic or a BCL-2/BCL-XL inhibitor. These have both been studied in phase 2 trials, [as well as] in phase 3 trials.

In the phase 2 trials, [these agents] have been studied in different settings. They are now being studied from a registrational perspective in the front line. The results with pelabresib and ruxolitinib in the front line in the phase 2 [MANIFEST trial (NCT02158858) demonstrated] a 68% spleen volume reduction rate [of at least 35% (SVR35)] and a 56% total symptom score [TSS] reduction [of at least 50% (TSS50)] at 24 weeks, much higher than we would expect with ruxolitinib alone. [In the phase 2 REFINE trial (NCT03222609)] with navitoclax, [by week 24], we saw a [63%] SVR35 rate and a [41%] TSS50 reduction in that frontline cohort. The pelabresib [trial] is larger, with significantly more patients. However, these are both exciting combinations that we await the phase 3 results from.

As research continues and other trials are launched, will we begin to see research depart from enrolling all-comers and instead having criteria driven by specific subsets? What research supports this approach?

We as a field need to go that way. We need to try and identify subsets that benefit from certain interventions. The field is not there yet. There are 3 kinds of trials primarily being pursued. One is frontline trials. These tend to use JAK inhibitor–based combinations. Another adds an investigational agent to a JAK inhibitor. Most of these have used ruxolitinib in the suboptimal setting, [in patients with] insufficient responses to the JAK inhibitor alone. The third is when the JAK inhibitor has been discontinued for resistance or intolerance, or the patient is not eligible for [treatment with] one. In that setting, several single agents have been investigated. Those are the 3 basic [trial] paradigms.

There are also trials for anemia. Those have been the ways that [researchers] have thought of the patient populations. We are not at a point yet where we have biologically stratified [these populations], but that’s important.

However, we are naturally seeing the end points of our registrational trials start to evolve. There was a time when it was always about spleen and symptoms. Now, it’s a little different. For example, [the pivotal MOMENTUM trial (NCT04173494) investigating] momelotinib, which is widely expected to be approved [in September], used only symptoms as the primary end point. [Factors such as] spleen [volume reduction] and anemia were key secondary end points.

Even more remarkably, imetelstat, a telomerase inhibitor being studied in the JAK inhibitor progression setting, is in a phase 3 pivotal trial [NCT04576156] with [overall] survival as the primary end point. We are seeing some movement there, but we are not defining subsets, genomically or biomarker wise, to study specific drugs yet.

How does the combination of ruxolitinib and navitoclax compare with what has been seen with ruxolitinib and pelabresib?

With ruxolitinib and pelabresib, we have information on significantly more patients. The frontline cohort of the phase 2 trial had 84 patients. [This trial showed] a 68% [SVR35 rate] and a 56% TSS[50] rate. By contrast, the navitoclax study in the front line with ruxolitinib was smaller, with 34 patients. In those patients, the spleen response rate was [63%], but the TSS rate was a little lower, at [41%].

Where this becomes important is [when we] consider what this means with the backdrop of what ruxolitinib alone can give [to patients]. In the [phase 3] COMFORT-I trial [NCT00952289] in 2012, we saw ruxolitinib yielding a 41.9% SVR35 rate and a 45.9% TSS50 rate at 24 weeks. That’s the benchmark that [researchers] use to compare these combination therapies to.

What ongoing myelofibrosis research at MD Anderson would you like to highlight?

We are participating in most of the exciting trials in the field. First, I would like to call out the Incyte ACVR1/ALK2 inhibitor, which I presented the results of at the 2023 ASCO Annual Meeting. This is an interesting compound that nicely complements ruxolitinib by addressing anemia.

Then, we have some of the pivotal trials I’ve alluded to. We have the imetelstat phase 3 trial, as well as the phase 3 BOREAS trial [NCT03662126] with navtemadlin [KRT-232], an MDM2 inhibitor. Those are for patients in the post–JAK inhibitor setting. We also have the INDEPENDENCE trial [NCT04717414], which is the pivotal phase 3 trial with luspatercept-aamt [Reblozyl]. Going back to the anemia theme, this is a placebo-controlled trial in patients receiving JAK inhibitors who require transfusions.

As we get into some of the more exciting new kids on the block, I will mention TP-3654. This is a PIM kinase inhibitor from Sumitomo [and] a relatively new target. However, some exciting results were already reported at the 2022 ASH Annual Meeting. We just opened that trial and are looking forward to enrollment.

What main message would you like colleagues to apply to their practice when treating patients with myelofibrosis?

This is an exciting time in the myelofibrosis drug development space. It’s almost mind boggling how many drugs and different mechanisms are being pursued. Even immunotherapies are here, with the vaccine trials against mutant calreticulin, or [treatments using] umbilical cord blood cells, which are regulatory T cells. We’re in a different era where we have options, albeit in trials, for virtually every type of patient. For example, with certain drugs, we are starting to see a platelet improvement signal. More than ever, referring patients for clinical trials is of paramount importance today.

References

1. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated April 6, 2023. Accessed June 19, 2023. https://clinicaltrials.gov/ct2/show/NCT04603495
2. Study of oral navitoclax tablet in combination with oral ruxolitinib tablet when compared with oral ruxolitinib tablet to assess change in spleen volume in adult participants with myelofibrosis (TRANSFORM-1). ClinicalTrials.gov. Updated April 27, 2023. Accessed June 19, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04472598